Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations

Yali Xue¹, Massimo Mezzavilla^{1

2}, Marc Haber¹, Shane McCarthy¹, Yuan Chen¹, Vagheesh Narasimhan¹, Arthur Gilly¹, Qasim Ayub¹, Vincenza Colonna^{1

3}, Lorraine Southam^{1

4}, Christopher Finan¹, Andrea Massaia^{1

5}, Himanshu Chheda⁶, Priit Palta^{6

7}, Graham Ritchie^{1

8

9}, Jennifer Asimit¹, George Dedoussis¹⁰, Paolo Gasparini¹¹, Aarno Palotie^{1

6

12

13

14

15

16}, Samuli Ripatti^{1

6

17}, Nicole Soranzo^{1

18}, Daniela Toniolo¹⁹, James F Wilson^{9

20}, Richard Durbin¹, Chris Tyler-Smith¹, Eleftheria Zeggini¹

Affiliations

¹ The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
² Institute for Maternal and Child Health, IRCCS Burlo Garofolo, University of Trieste, 34137 Trieste, Italy.
³ Consiglio Nazionale delle Ricerche, Istituto di Genetica e Biofisica 'Adriano Buzzati-Traverso', via Pietro Castellino 111, 80131 Napoli, Italy.
⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁵ National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
⁶ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 8, 00290 Helsinki, Finland.
⁷ Estonian Genome Center, University of Tartu, 23B Riia Street, 51010 Tartu, Estonia.
⁸ European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
⁹ MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
¹⁰ Department of Nutrition and Dietetics, Harokopio University Athens, Athens, Eleftheriou Venizelou 70, Kallithea 176 76, Greece.
¹¹ Medical Genetics, DSM, University of Trieste and IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Burlo Garofolo Children Hospital, Via dell'Istria, 65, 34137 Trieste, Italy.
¹² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹³ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA.
¹⁴ The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA.
¹⁵ Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹⁶ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹⁷ Department of Public Health, University of Helsinki, Helsinki FI-00014, Finland.
¹⁸ Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
¹⁹ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy.
²⁰ Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG Scotland, UK.

PMID: 28643794
PMCID: PMC5490002
DOI: 10.1038/ncomms15927

Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations

Yali Xue et al. Nat Commun. 2017.

. 2017 Jun 23:8:15927.

doi: 10.1038/ncomms15927.

Authors

Affiliations

¹ The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
² Institute for Maternal and Child Health, IRCCS Burlo Garofolo, University of Trieste, 34137 Trieste, Italy.
³ Consiglio Nazionale delle Ricerche, Istituto di Genetica e Biofisica 'Adriano Buzzati-Traverso', via Pietro Castellino 111, 80131 Napoli, Italy.
⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁵ National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
⁶ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 8, 00290 Helsinki, Finland.
⁷ Estonian Genome Center, University of Tartu, 23B Riia Street, 51010 Tartu, Estonia.
⁸ European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
⁹ MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
¹⁰ Department of Nutrition and Dietetics, Harokopio University Athens, Athens, Eleftheriou Venizelou 70, Kallithea 176 76, Greece.
¹¹ Medical Genetics, DSM, University of Trieste and IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Burlo Garofolo Children Hospital, Via dell'Istria, 65, 34137 Trieste, Italy.
¹² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹³ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA.
¹⁴ The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA.
¹⁵ Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹⁶ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹⁷ Department of Public Health, University of Helsinki, Helsinki FI-00014, Finland.
¹⁸ Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
¹⁹ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy.
²⁰ Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG Scotland, UK.

PMID: 28643794
PMCID: PMC5490002
DOI: 10.1038/ncomms15927

Abstract

The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Figure 1. General characteristics and demographic history of isolated and matched general populations.**
(a) Geographical locations of samples. The base map was plotted in R using the mapdata package and circles were added using Photoshop. (b) PCA using common variants. (c) PCA using low-frequency variants. (d) Sharing of rare variants within and between populations. Upper left triangle: f₂ variants; lower right triangle f₃–f₁₀ variants. (e) Effective population size (Ne) inferred from IBDNe for UKO and UKG during the past nine KY. (f) The lowest Ne inferred by IBDNe for all populations for the past three KY, plotted as a function of the time at which it occurred.

**Figure 2. Isolation index (*Isx*) and its correlation with other genetic measures.**
(a) Information summarized in *Isx*. (b) Example of the correlation between *Isx* and other statistics, here *DVxy-coding*. (c) Summary of the correlations between *Isx* and other population-genetic statistics. All the correlation coefficients are high and statistically significant.

**Figure 3. Purifying selection in the isolates and general populations.**
(a) *Rxy*-missense statistic in each isolate, showing no evidence for increased genetic load in the isolates. The mean and s.d. for each *Rxy* value from 100 bootstraps are shown. (b) *DVxy-wg* (*DVxy*-whole genome) statistic in isolates and general populations, stratified by CADD score, showing enrichment of highly functional low-frequency variants. (c) *DVxy-coding* statistic in isolates and general populations, showing enrichment of low-frequency missense variants in isolates. (d) *SVxy*-missense statistic in each isolate, showing relaxation of purifying selection in isolates in singletons. The s.e.'s for both *DVxy* and *SVxy* were calculated by randomly sampling data from 20 chromosomes 100 times. All of these analyses are based on the minimum-sample-size data set (36 individuals from each population).

See this image and copyright information in PMC

References

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1. Hatzikotoulas K., Gilly A. & Zeggini E. Using population isolates in genetic association studies. Brief Funct. Genomics 13, 371–377 (2014). - PMC - PubMed
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Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations

Affiliations

Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources